It has been estimated that millions are infected with Leishmania and tens of millions more with the related Trypanosomes. Perhaps a half of billion people live in areas endemic to these parasites and are at risk. The established anti-Leishmania compounds are not completely efficacious and adverse reactions have been documented. Similar problems occur with the drugs used for the other Trypanosomes. The purine analogs allopurinol and allopurinol riboside, on the other hand, are toxic to these organisms but relatively benign to humans and have demonstrated some success in the treatment of these parasitic infections. TOR, an atypical multi drug resistance factor, elicits resistance to toxic nucleoside as well as to Pentostam, Amphotericin B and a number of other structurally unrelated compounds. The specific aim of this proposal is to determine how TOR exerts its effects. This will be accomplished by determining the fate of the adenosine permease in Leishmania which express more or less TOR than do wild type cells. Western and northern blotting and ribonuclease protection assays will enable us to determine how TOR affects the activity of this reporter permease. The broad, long term objectives are to manipulate through TOR the sensitivity of Leishmania to toxic nucleosides and the other clinically proven anti-Leishmania compounds. It may be possible through TOR to reduce the purine transport capability and starve the parasite of an absolutely essential nutrient.